Pyrimidinedione derivatives are BCS II type drugs possessing low solubility and high permeability. One of the common problems of poorly water-soluble drugs is that they provide low bioavailability and/or higher variability in bioavailability resulting from poor water solubility and low dissolution.
Formation of a soluble salt form for an insoluble compound is often a means to increase drug solubility in an aqueous medium, and hence improve dissolution rate and ultimately enhance bioavailability. In some cases, however, such soluble salt may also have high bio-variability or in worst case scenario, the bioavailability of the drug is not improved at all. However, salt forms of pyrimidinedione derivative are prone to converting back to a free acid form, especially in the acidic environment of the stomach, forming a precipitate that cannot be readily absorbed. Upon exposure to an aqueous medium, the salt undergoes a dissolution process which includes dissolving of the solid particle followed by diffusion of the dissolved drug. The latter is often controlled by a diffusion layer environment. Within the diffusion layer, the salt might be dissociated to a non-ionized form which may achieve supersaturation and then precipitate out either on the exterior surface of the salt particle or in the bulk medium, preventing further dissolution of the salt, and therefore resulting in low bioavailability with high variability by the approaches of reducing active pharmaceutical ingredient (API) particle size and/or modulating the diffusion layer environment to enhance drug dissolution rate and ultimately in vivo bioavailability.
Formulation techniques used to prevent free acid conversion of the active agent and to enhance its release from the dosage form often disrupts other properties critical to the tablet manufacturing process such as flowability and compaction. Properties such as flowability of formulation material will impact such things as control of the tablet weight, the uniformity of the content of the dosage unit and the ease with which the formulation is able to be fed into a die for compression. Compaction is another critical property necessary to produce tablets with adequate tensile strength and hardness. In addition, it is often desirable to increase the amount of active agent in the dosage form to achieve adequate efficacy in human without increasing the pill size and burden.
There are challenges to develop orally bioavailable dosage forms containing pyrimidinedione compounds due to their extremely low intrinsic aqueous solubility. Although the potassium- or sodium—salt of certain pyrimidinedione compounds possesses a rapid dissolution to form a supersaturated state in aqueous media, the formation of the insoluble free acid form in the physiological GI environment with pH<8 (based on their pKa1>8.3) upon dissolution is inevitable. Therefore, rapid conversion of the salt into the free acid form with essentially extremely slow dissolution usually results in low oral bioavailability. There is therefore a need for improved formulations for poorly water-soluble drugs, and identifying appropriate functional excipients and developing a highly bioavailable drug product of pyrimidinedione compounds continues to be a challenging endeavor.